HLA-E-VL9 antibodies enhance NK cell and CD8 ⁺ T cell cytotoxicity against HIV-infected CD4 ⁺ T cells

A major natural killer (NK) cell and CD8 ⁺ T cell checkpoint is mediated by the inhibitory receptor NKG2A/CD94 and its ligand, HLA-E complexed with 9 amino acid HLA-Ia leader sequence-derived peptides termed VL9 (HLA-E-VL9). Here, we used structure-based design and high throughput library screening to generate antibodies that block NKG2A/CD94 interactions, resulting in direct NK and CD8 ⁺ T cell cytotoxicity, and trigger NK cell antibody-dependent cellular cytotoxicity (ADCC). Anti-HLA-E-VL9 antibodies limited HLA-E-VL9+ tumor growth in mice, demonstrating checkpoint inhibition activity in vivo . HLA-E-VL9 was found to be expressed on HIV-infected cells, and its engagement by HLA-E-VL9 antibodies eliminated infected cells by NK-mediated ADCC. HLA-E-VL9 antibodies also enhanced the killing of HIV-infected cells by NKG2A/CD94 ⁺ CD8 ⁺ T cells targeting a novel HLA-E binding HIV Rev-derived epitope. Therefore, anti-HLA-E-VL9 antibodies represent a novel approach to eliminate pathogenic target cells by enhancing NK and CD8+ T cell function and promoting ADCC.